tbuckley/cabot-search huggingface dataset:
Patient-derived skin MicroOrganoSpheres and clinical response to immunotherapy.
Authors: Rikhia Chakraborty, Katerina Fagan-Solis, Jessica DeVilla, Timothy Recaldin, Michael Bscheider, Nikolche Gjorevski, Aaron Fullerton, Rodney Prell, Zia Khan, Zhaohui Wang, Shengli Ding, Carolyn Glass, William Jeck, Shannon J. McCall, Georgia Beasley, Rajat Mohindra, Shiaowen David Hsu, G Scott Chandler, Xiling Shen, Adrian B Roth
Journal: Journal of Clinical Oncology (2023)

2588 Background: Immunotherapies, including immune checkpoint inhibitors (ICI), have revolutionized the treatment of many cancers, producing significant improvements in survival in patients with many different cancers. However, the intended anti-tumor effects also result in a unique form of autoimmunity, known as immune-related adverse events (irAEs), which have emerged as a limiting factor for many immunotherapies. Cutaneous irAEs (cirAEs), the most frequently occurring ICI–related toxicities, have been associated with improved efficacy and survival but, in their severe forms, require systemic steroids and have in cases led to premature ICI discontinuation and fatality. There is a need for both robust biomarkers and adequate models that effectively predict which patients who develop irAEs may have improved outcomes. Methods: Using a microfluidic droplet technology that generates "mini" patient-derived organoids called MicroOrganoSpheres (MOS), we successfully generated skin MOS from skin biopsy samples in both healthy skin and tumor-involved skin that sustain the original patient skin immune microenvironment over three weeks. Using this model, we assessed skin cell toxicity and cytokine release in response to ICI and targeted therapies. Results: Clinical responses were largely consistent with the skin and tumor MOS assay readouts, indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Matched pairs of patient melanoma and skin MOS showed good concordance with patient outcome indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Enrichment of genes associated with atopic dermatitis, vitiligo, and psoriatic dermatitis were observed in MOS generated from skin of an ICI-sensitive patient compared to the MOS generated from skin of an ICI-resistant patient. These results indicated that the skin MOS platform can potentially predict the dermatological toxicity of ICI. As the MOS assay can be completed within 12 days after biopsy acquisition, this novel technology may enable personalized medicine approaches by prediction of cirAEs and efficacy for individual patients. Conclusions: This is the first study to date demonstrating the application of a patient-derived immune competent skin model deployable for assessing ICI efficacy and toxicity response. Matched tumor skin MOS from the same patients recapitulated the clinically observed association between ICI efficacy and toxicity and may provide key indicators for prospective irAE-predicting clinical trials.
The impact of clinical equations on carboplatin dosing: A systematic review to determine appropriate dosing of carboplatin in adult cancer patients.
Authors: Maya Leiva, Sabrine Yamauchi
Journal: Journal of Clinical Oncology (2023)

e15005 Background: The Calvert formula is used to estimate the carboplatin dose needed to achieve the desired Area Under the Curve (AUC) despite little consensus on which estimated Glomerular Filtration Rate (eGFR) equation best reflects renal clearance. Cockcroft-Gault (CG) is often used when calculating estimated Creatinine Clearance (CrCl) for the Calvert formula. Equations like Modification of Diet in Renal Disease or CKD-EPI (based on serum creatinine (SrCr) or cystatin C), take into account parameters such as race, gender, weight. We compared several publications to determine the most effective dosing strategy for carboplatin. Methods: Utilizing PubMed, 19 articles were found with the keywords “carboplatin, dosing, eGFR, measure GFR, creatinine clearance, muscle mass.” Our inclusion criteria consisted of being published within the last 10 years, included carboplatin dosing, and evaluated either measured GFR, measured CrCl, carboplatin clearance or toxicities caused by carboplatin. Studies not meeting these parameters were excluded. Of the 19 articles, 11 articles were identified regarding the accuracy of eGFR and its effects on carboplatin dosing and/or dose limiting toxicities. An extensive literature review of each article was used to find a consensus among the clinical equations used in carboplatin dosing. Results: There remains no consensus on the most accurate eGFR equation. Eight studies evaluated accuracy of varying equations in estimating GFR, creatinine clearance or carboplatin clearance. Two studies created new equations (one measuring GFR and the other measuring CrCl) and compared them to current equations for accuracy. Ultimately, only two studies were in agreement that CKD-EPI was the most viable option when GFR uses SrCr. Based on four studies, CG is an inadequate measurement of eGFR. CG ranked low due to a high mean percent error when compared to measured GFR, indicating a larger discrepancy between measured GFR and the estimated value of CG, as compared to other equations. Three of the studies evaluated for a correlation in skeletal muscle mass and hematological toxicities, indicating that changes in muscle mass could correlate with hematological toxicities. One small study developed a new equation based on muscle mass and SrCr and showed positive results for accuracy when compared to measure CrCl. Conclusions: Although a definitive equation to estimate renal clearance could not be established, equations like CG have limited accuracy due to race, weight, age, and gender. The single study that utilized muscle mass demonstrated the most promise and presents a better option for patients, particularly when muscle mass changes over time. Other studies illustrated that muscle mass is significantly correlated with carboplatin toxicity and should be considered for future studies to determine the safest method for dosing carboplatin.
MyTACTIC: Afficacy and safety of atezolizumab (atezo) + chemotherapy (chemo) in patients (pts) with advanced unresectable/metastatic solid tumors with high tumor mutational burden (TMB-H) or high microsatellite instability (MSI-H)/deficient mismatch repair (dMMR).
Authors: David R. Spigel, Maen A. Hussein, Richard Zuniga, Daruka Mahadevan, Robert Winn, Walter C. Darbonne, Bongin Yoo, Young Kim, Zach Whitehead, Ari M. Vanderwalde
Journal: Journal of Clinical Oncology (2023)

2612 Background: MyTACTIC (NCT04632992) is a phase II, non-randomized, multi-arm basket study evaluating targeted therapies as single agents or combinations in pts with advanced solid tumors with specific biomarkers. We present the efficacy and safety of arm E from MyTACTIC: atezo + chemo in pts whose tumors have TMB-H and/or MSI-H/dMMR. Methods: Enrolled pts were ≥18 years old, with histologically/cytologically confirmed advanced unresectable/metastatic solid tumors with TMB-H (TMB≥10 mut/Mb) and/or MSI-H/dMMR and ECOG PS ≤2; those with symptomatic/actively progressing CNS metastases were excluded. Pts received intravenous atezo 1200 mg every 21 days and physician’s choice chemo (docetaxel; paclitaxel; capecitabine) until progressive disease (PD), toxicity or death. Primary endpoint: investigator-assessed confirmed objective response rate (cORR). Secondary endpoints included disease control rate (DCR; confirmed complete response [CR] + partial response [PR] + stable disease [SD] or non-CR/non-PD for ≥70 days), duration of response (DOR), progression-free survival (PFS) and safety. Results: At data cutoff (May 16, 2022), 25 pts with 10 tumor types had received atezo + chemo. Median age was 69 years (range 37–83), 88% of pts had ECOG PS ≤1 and 20 pts with metastatic disease had a median of 1 prior line of therapy (range 1–4). Twenty-three pts had TMB-H (2 missing), 7 had MSI-H and 7 had dMMR (12 missing); 7 pts had TMB-H and MSI-H/dMMR. cORR was 28.0% (7/25; 95% CI 12.1–49.4), including 1 CR (colon cancer) and 6 PRs. Responses were observed in 6/10 tumor types studied. cORR was 12.5% in pts with TMB-H alone (2/16) and 71.4% (5/7) in pts with TMB-H and MSI-H/dMMR. DCR was 32.0% (8/25; 95% CI 14.9–53.5). Median DOR and median PFS were 7.4 months (95% CI 7.4–not estimable) and 3.9 months (95% CI 2.2–8.4), respectively. The safety profile of atezo + chemo was consistent with previous reports for this combination. The most common treatment-related adverse events (TRAEs) were diarrhea (60%) and fatigue (32%). Grade 3/4 TRAEs occurred in 32% of pts and there were no serious or grade 5 TRAEs. Conclusions: In this small cohort, treatment with atezo + chemo demonstrated clinical activity in pts with advanced solid tumors with TMB-H and/or MSI-H/dMMR. Responses were observed in different tumor types and were numerically higher in pts whose tumors had both biomarkers vs those with TMB-H alone. Further analyses with a larger cohort and longer follow-up will be required to confirm these results. Clinical trial information: NCT04632992 . [Table: see text]
Comprehensive multigene profiling impact on clinical decisions in patients with advanced cancers: A multicenter, retrospective analysis.
Authors: Olesya Kuznetsova, Maxim Ivanov, Alexey Tryakin, Alexandra Lebedeva, Ekaterina Ignatova, Mikhail Fedyanin
Journal: Journal of Clinical Oncology (2023)

e15163 Background: Comprehensive molecular profiling (CMP) via next generation sequencing (NGS) is currently applied in clinical practice and has enabled the detection of biomarkers of response to targeted treatment. Given the lack of the data about optimal range of analyzed alterations, the clinical usefulness of CMP has not been established. To address the challenges in incorporating genomics in treatment of oncology patients, we conducted a retrospective study. Methods: Preliminary analysis of NGS reports and clinical data of patients with advanced solid tumors was performed. CMP was conducted in 261 cancer patients (non-small cell lung cancer - 30,6%, colorectal cancer - 24,8%, pancreatic cancer - 7,4%, breast cancer- 6,2%; 59,3% were female, median number of prior systemic treatment lines was 2 (0-12)). In the present study, tumor molecular profile analysis was performed using 160 - 400 gene NGS panels, containing the majority of clinically significant genes for cancer treatment selection. We assessed the percentage of patients who were recommended to receive molecularly-matched therapy (MMT) after CMP, immunotherapy (IT) distribution of recommended therapies according to ESCAT tiers, median progression-free survival (PFS) – ratio ( = PFS after CMP / PFS before CMP, PFS2/PFS1), median PFS2. Results: MMT after CMP was recommended for 55 (21,1%) patients. ESCAT tiers could be assessed in 48 MMT patients (87%). For 31% of patients, administered therapy was considered as ESCAT I tier recommendation (data on mPFS2/1, mPFS2 not available). ESCAT tiers II, III, IV and IT administration were considered in 31, 8, 8 and 22% of patients respectively (detailed data is presented in Table 1). Most commonly altered genes were TP53 (53%), RAS (29%), APC (18%), CDKN2A/B (16%), PIK3CA(14%), NF1 (10%), BRCA1/2 (9%). Positive predictive factors for MMT after CMP were MSI-high status (HR 0,13, 95% CI 0,03 - 0,67), presence of EGFR alteration (HR 0,32, 95% CI 0,12 - 0,86). Presence of RAS mutation was considered a negative predictive factor (HR 2,78, 1,07 - 7,26). Conclusions: Available NGS panels offer a wide range of analyzed alterations that are not feasible in clinical practice. Most of the alterations that can cause impact on treatment plan can be detected with other methods than NGS. Further studies are needed to determine optimal range of alterations depending on tumor site. [Table: see text]
Comprehensive multi-omic testing from a single laboratory to provide information in ovarian cancer.
Authors: Debora Mancini-Dinardo, Lauren Lenz, Matthew Comeaux, Shanell Hatcher, Alexander Gutin, Anne Thomsen, Ashley Wroblewski, Alexzandra Eich, Tyson Moll, Lynette Poyser, Thomas Paul Slavin, Kirsten Timms
Journal: Journal of Clinical Oncology (2023)

e15045 Background: Molecular profiling of ovarian tumors allows for personalized disease treatment but often requires testing from multiple laboratories. This study highlights results from a molecular testing pathway that reports on germline and tumor mutations, microsatellite instability (MSI), tumor mutation burden (TMB), and homologous recombination deficiency (HRD) to guide optimal treatment selection. Methods: Samples from a consecutive prospective cohort of ovarian cancer patients were collected and tested with an HRD companion diagnostic (CDx) test (FDA-approved) that assesses genomic instability score (GIS) via a 3-biomarker signature and tumor mutation screening using a 523-gene DNA and a 55-gene RNA panel to identify clinically actionable test results using Association for Molecular Pathology (AMP) tiering. Some patients also received germline analysis via a 48-gene panel or a BRCA1/2 CDx. Clinical data (tumor stage and grade, histological subtype) were compared using logistic regression models. GIS distributions were compared using Kolmogorov-Smirnov tests. Results: To date, results from 389 eligible patients have been analyzed. Table 1 shows the primary results of molecular testing. Tumor subtype analyses revealed that high-grade serous subtype was tested most frequently (66.1%). Some less-represented subtypes (e.g., carcinoscarcoma, mucinous) appeared to have GIS distributions like high-grade serous, while others generally have low GIS. GIS distributions were significantly different in high-grade (vs moderate and vs low-grade) and stage I (vs the similar stages II-IV) tumors. Tier 1A/B mutations were observed in 16.7% of tumors; 36.9% of those were non- BRCA pathogenic variants/mutations. Distributions of histological subtype and grade were significantly different between t BRCA+ and non- BRCA samples with other Tier 1A/B mutations. Mutations were observed in 9.0% of germline tests; tumor mutation testing identified all germline variants except for a PMS2 multi-exonic deletion. Conclusions: Multi-omic testing found ~30% of ovarian cancer patients received a clinically actionable test result (HRD was the most common) and ~90% of results conferred eligibility for clinical trials. Incorporation of germline testing and RNA analysis identified unique actionable findings. A single source for comprehensive testing combined with a single integrated report facilitates rapid testing, test interpretation, and treatment choice. [Table: see text]
Effect of locoregional injection of RNA oligonucleotide targeting carbohydrate sulfotransferase 15 on both tumoral and lymph node MDSCs and T cell infiltration in pancreatic tumor in mice.
Authors: Juanjuan Ye, Futoshi Suizu, Keiko Yamakawa, Motohiko Kato, Takayoshi Tsuchiya, Hiroyuki Yoneyama, Naohisa Yahagi
Journal: Journal of Clinical Oncology (2023)

e16310 Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and is responsible for tumor matrix remodeling. Intratumoral injection of CHST15 siRNA was shown to increase tumor-infiltrating T cells in patients with pancreatic cancer in the phase I/IIa study. However, the mechanism underlying the enhanced T cell accumulation is not fully explored. Here we investigated the effect of locally injected CHST15 siRNA on modulating tumor immune microenvironment in mice. Methods: For in vivo pharmacokinetics after a single local injection of CHST15 siRNA to normal C57BL/6J mice, RNA oligonucleotides were isolated from tissues and detected by HPLC. Mouse pancreatic cancer KPC cells were implanted subcutaneously into the left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. From week 1, intratumoral injections with 1 mg/mL of CHST15 siRNA or vehicle were performed twice a week for 2 weeks and mice were sacrificed at week 3. In separate experiments, human BxPC-3 cells were implanted subcutaneously in T cell-deficient nude mice, and the effect of intratumoral injections of CHST15 siRNA or vehicle for 2 weeks was also investigated. Immunohistochemical staining was performed for the tumor and tumor-draining lymph node (TDLN). Results: CHST15 siRNA was detectable in not only the local sites but also the draining LNs of normal mice 1 and 4 hours after locoregional injection. In the KPC-implanted syngeneic mouse model, CHST15 siRNA showed significant tumor growth inhibition compared to the vehicle. In tumor, CHST15 was expressed by tumor cells, and to a lesser extent, Ly6C/G + MDSCs. CHST15 siRNA altered tissue remodeling by repressing dense fibrotic architecture and NETosis. CHST15 siRNA significantly diminished Ly6C/G + MDSCs while increasing CD4 + and CD8 + T cells. In TDLN, CHST15 was expressed by Ly6C/G + MDSCs. Locally injected CHST15 siRNA markedly diminished Ly6C/G + MDSCs, while increasing Ki-67 + proliferating CD4 + and CD8 + T cells. In the BxPC-3-implanted nude mouse model, locally injected CHST15 siRNA repressed excessive fibrosis and NETosis in tumor, diminishing both tumoral and TDLN MDSCs, but tumor growth inhibition was marginal. These results suggest that locally injected CHST15 siRNA could enter into TDLN, directly diminishing CHST15 + MDSCs, and expanded T cells. Tumor growth inhibition was largely T-cell medicated. Conclusions: The present study demonstrated that CHST15 siRNA locally and remotely diminished MDSCs, leading to the enhancement of anti-tumor T cell activity. A novel role of locally-delivered RNA oligonucleotide is suggested.
Treatment of chronic hepatitis C virus infection to increase access to cancer clinical trials in patients with hematologic malignancies: A prospective observational study.
Authors: Khalis Mustafayev, Aung Naing, Sheeba K. Thomas, Krina K. Patel, Naveen Pemmaraju, Naval Guastad Daver, Ying Jiang, Eduardo Yepez Guevara, Harrys A. Torres
Journal: Journal of Clinical Oncology (2023)

3142 Background: Most cancer patients with chronic hepatitis C virus (HCV) infection are excluded from cancer clinical trials (CCTs). The use of direct-acting antivirals (DAAs) to eradicate HCV and allow access to CCTs in HCV-infected cancer patients has not been studied. We aimed to evaluate the efficacy and safety of DAA treatment to increase access to CCTs in patients with chronic HCV infection and hematologic malignancies (HM). Methods: HCV-infected patients with HM seen at MD Anderson Cancer Center between 01/01/2016 and 01/31/2023 were enrolled in a prospective observational study. Those initially excluded from CCTs and then treated with DAAs to allow that cancer treatment were further analyzed (cases). HCV-infected cancer patients treated with DAAs but never enrolled in CCTs were used as controls. The 1:1 matching between cases and controls was based on the cancer type and stage, history of &gt; 3 types of chemotherapy, and presence of cirrhosis. The primary outcomes were the efficacy and safety of DAAs. The secondary outcomes were overall survival (OS) and progression-free survival (PFS). Results: Twenty-four patients with HM initially excluded from CCTs because of HCV were enrolled. Twelve of them (50%) received DAAs to have access to CCTs and they were matched to 12 controls. Most of the cases were men (10; 83%), white (6; 50%), non-cirrhotic (10; 83%), and with HCV genotype 1 (9; 75%). Most patients in the control group were men (7; 58%), white (9; 75%), non-cirrhotic (8; 67%), and with HCV genotype 1 (9; 75%). Among the entire study group, adverse events occurred in 6 of the 24 patients (25%), and all were grade 1-2. No HCV-associated liver failure or death occurred. The overall sustained virologic response (microbiologic cure) after completion of antiviral therapy was 92%. Median OS was 74 months in the cases vs 52 months in the controls, median PFS was 30 months in the cases vs 33 months in the controls. When compared to controls in multivariate analysis, cases had significantly better OS (hazard ratio = 0.23, 95% CI = 0.06 to 0.85, p = 0.027). No significant differences were noted in PFS (p=0.13). Death due to progressive HM occurred in all 12 controls (100%) but only in 4 cases (33%) (p=0.001). Conclusions: DAA treatment increases access to CCTs and improves OS in patients with chronic HCV infection and HM. HCV infection should not be considered a contraindication to investigational cancer treatment. The use of DAAs to facilitate access CCTs could become one of the most common indications for DAAs in HCV-infected cancer patients.
The efficacy of autologous hematopoietic cell transplantation in standard risk multiple myeloma refractory to multiple therapies.
Authors: Hussein Awada, Adel Hajj Ali, Chadi Tabaja, Jack Khouri, Faiz Anwer
Journal: Journal of Clinical Oncology (2023)

e20039 Background: Patients with multiple myeloma (MM) of standard risk (SR) cytogenetics generally experience better outcomes compared to high risk (HR) disease. However, it remains poorly understood why outcomes amongst SR MM patients are highly variable, especially after autologous hematopoietic cell transplant (AHCT). Here, we investigated the outcomes of AHCT in SR MM patients who failed multiple therapies pre-AHCT. Methods: We reviewed all MM patients who underwent AHCT at the Cleveland Clinic between January 1, 2011 and January 15, 2021. Demographic characteristics, comorbidities, International Scoring System (ISS) stages, serum and bone marrow studies, pre-AHCT treatments, and maintenance therapy were obtained from electronic medical records. SR MM was considered in patients without t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Patients were divided into 4 groups of 1, 2, 3 or ≥4 therapies pre-AHCT. The primary outcome studied was median time to either progression or death, reported as time to event (TTE) and determined by Kaplan Meier analysis. Results: We reviewed a total of 517 patients, among whom 279 were determined as SR MM and hence were included in our analysis. Of this cohort, 188 patients received a single line of therapy, 63 patients received 2 lines, 32 patients received 3 lines, and 10 patients received ≥4 lines pre-AHCT. The baseline demographic and clinical characteristics were then compared between the groups and they showed similar age at AHCT (61 vs 60.6 vs 59.6 vs 59.9 years, P=0.8), albumin levels (&lt;3.5 g/dL 22.4 vs 22.8 vs 16.7 vs 50%, P=0.2), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score (≥3 40.4 vs 47.6 vs 65.6 vs 60%, P=0.1), Male preponderance (54.8 vs 65.1 vs 65.6 vs 50%, P=0.4), ethnicity (White 82.4 vs 84.1 vs 78.1 vs 90%, P=0.8), ISS stages (P=0.7), MM immunoglobulin subtype (IgG 28.7 vs 20.6 vs 18.8 vs 30%, P=0.6), on single agent maintenance (8.9 vs 19 vs 13.8 vs 0%, P=0.1), respectively. The only significant differences between the four groups were smoking history (34.9 vs 53.2 vs 40.6 vs 60%, P=0.045) and time from diagnosis to transplant (&gt;12 months 21.3 vs 44.4 vs 75 vs 100%, P&lt;0.0001) reflecting resistance to therapies. Kaplan-Meier analysis for median TTE revealed a significantly shorter median TTE for the ≥4 therapies group at 8 months vs 54.5, 55.9 and 67.7 months for the 1, 2, and 3 pre-AHCT therapies groups. Conclusions: SR MM patients who require ≥4 therapies pre-AHCT have poor outcomes post-transplant. We suggest the use of AHCT early in the course of myeloma treatment given the shorter time to progression as also shown in randomized trials.